Tomorrow, I will be speaking at the Marshal M. Weinberg Seminar on Optogenetic Manipulation of the Brain at the University of Michigan – not a subject I must admit that I am that familiar with.  Fortunately, there are other speakers who will be doing much of the heavy-lifting, including Karl Deisseroth – a leading optogenetics researcher, and author of a recent in-depth article in Scientific American on controlling the brain with light.  My role – I suspect – is to bring a broader social and technological perspective to the benefits and risks of this rapidly emerging field as part of the closing panel discussion – neatly titled “Mind Control: What do you think?”

Here, I must confess that I’m going to be relying an awful lot on the preceding talks to round off my education in optogenetics before I launch in.  But I have been doing some preparatory work on optogenetics, and in particular the plausibility of its possible use in manipulating brain function at a sophisticated level.

By way of background, optogenetics is a relatively young field that revolves around the study and use of specific genetic sequences – opsins – to enable the modulation of cellular and sub-cellular processes in the presence of light.  Its roots stem back to early research into optically-modulated biological processes in microorganisms.  But it wasn’t until a number of fields began to converge that the possibility of utilizing these seemingly esoteric processes began to emerge.

For decades now, it has been known that some microorganisms have the ability to respond to light by producing  proteins that switch or otherwise modify specific cellular processes. This might have remained a curiosity if it wasn’t for the increasing ability to cut and paste functional genetic sequences from one species to another, and the realization that to control many cell-level biological processes, fast, precisely timed pulses of light could provide a control mechanism that overcomes the limitations of electrical and chemical alternatives.  The result has been the emergence of optogenetics as a well-defined field – in Deisseroth’s words

“the use of optics and genetics to control well-defined events within specific cells of living tissue”.

Optogenetics includes the discovery and insertion into cells of genes that enable them to respond in specific ways to light… It also includes the technologies that enable the delivery of  light deep within complex organisms to control light-sensitive processes at the cellular level, and technologies for monitoring and assessing the results of this optical control.

One of the more high profile application areas of optogenetics is in understanding the brain and intervening in neural processes.  Deisseroth again:

What excites neuroscientists about optogenetics is control over defined events within defined cell types at defined times—a level of precision that is most likely crucial to biological understanding even beyond neuroscience. The significance of any event in a cell has full meaning only in the context of the other events occurring around it in the rest of the tissue, the whole organism or even the larger environment. Even a shift of a few milliseconds in the timing of a neuron’s firing, for example, can sometimes completely reverse the effect of its signal on the rest of the nervous system. And millisecond-scale timing precision within behaving mammals has been essential for key insights into both normal brain function and into clinical problems such as parkinsonism.

The possibilities here are tremendously exciting.  But they also raise whole rafts of questions over the dangers and ethics of meddling with the brain – and by extension the mind.  What are the possibilities of dual-use technologies that can lead to questionable as well as acceptable control?  Could optogenetic “mind control” lead to significantly altered personalities – and if so, who is responsible for the results?  Might optogeneticically modulated individuals be “hacked” – enabling third parties to gain control over their decisions and actions?  And what are the ethical boundaries to developing and using technologies that depend on genetic, physiological and psychological manipulation of subjects?

These are all questions that are ripe for serious discussion.  But to be productive, they must also be grounded in scientific and technological plausibility.  It’s easy to imagine what might be achieved by optogenetics through extrapolation and speculation.  But given realistic scientific and technological constraints, what is is plausibly likely to be achieved?

Reading up on the state of the science as it stands now, it seems that concerns over the nefarious use of optogenetics for sophisticated mind control are probably premature.  The brain is a hugely complex organ, and sophisticated as current technologies seem, we are still a long way from being able to understand, control and manipulate it with any real dexterity.  In fact, worrying too much about mind control at this point is probably the equivalent to jumping straight from using crude saws to amputate damaged limbs to worrying about the implications to advanced brain surgery.  Nevertheless, in preparation for tomorrow’s panel discussion, I though it worthwhile spending some time thinking about the technologies that could potentially bring sophisticated mind control closer to being a reality.

Over the next decade or so, getting new genetic sequences into neurons will probably be less of a challenge than getting short, precisely-timed pulses of light to neurons deep within the brain.  We already have a number of technology platforms that are actively being explored on this front.  On the other hand, the ability to channel pulses of light to small and highly localized volumes deep within the brain still presents huge challenges.  So what are the options here, and where might the technology develop?

Advances in fiber-optic probes are beginning to open up deep brain optical stimulation, and offer the possibility of stimulating relatively small volumes on demand.  But the spatial resolution achievable is still coarse, and will probably remain so as there is a limit to how many probes can be inserted into a brain.  This technology may well prove suitable for modulating brain function in very basic ways – possibly to a sufficient degree to aid patients with conditions such as Parkinson’s disease.  But insertion of fiber-optic probes lacks the finesse required for sophisticated manipulation.  And of course, there is the hassle of both inserting the probes, and having them present as a permanent fixture for as long as the stimulation is required.

High density and highly localized probes that are hard wired to the external world ideally requires a dense network of probes that are organically “grown” through the brain – a technology I am sure will remain in the realms of science fiction for my lifetime at least.  If such a technology could be developed, it would enable high spatial resolution optical stimulation, opening up the possibility of fine-tuning optogenetic control to small clusters of neurons.  But while nanoscale regenerative medicine is making interesting breakthroughs in self-assembling biocompatible structures, it is hard to imagine these translating into useable optogenetic neural nets any time soon.

There is another possible route to high resolution and highly localized stimulation though, which isn’t too dissimilar to the sci-fi concept of a optogenetic neural net.  Imagine that you could place the equivalent of millions of fiber optic probe tips through the brain, and then communicate with them wirelesly – you would have the equibalent of the neural net, without the net part.

Fanciful as it may sound, it’s and approach that has already been used to develop cellular and sub-cellular probes.  PEBBLE technology – Photonic Explorer for Biomedical use with Biologically Localized Embedding technology – has been under development for some years for tracking biological processes in situ.  Could a similar technology be used for wireless neurogenetic control?

Imagine a biologically benign nanoparticle that could be stimulated to emit light of a given wavelength in the presence of a specific electromagnetic field.  If these particles could be diffused throughout the brain, local stimulation might be possible by using focused electromagnetic fields.  Wireless optogenetic control.

Of course, there are tremendous technical barriers here – not least engineering particles that are able to pick up and respond to specific signals.  But our ability to engineer nanomaterials to exhibit non-liner interactions with electromagnetic fields and to exploit these interactions may help us to overcome overcome this particular barrier.  Even then though, there is the challenge of focusing these fields to within precise volumes within the brain in order to elicit the desired effect.

Plausible I suspect, but extremely time consuming and cumbersome.

But what if the nanoparticles could be programmed to respond to specific stimuli once in place?  Imagine a sophisticated nanoparticle that, in the presence of a high intensity electromagnetic field, can be programmed to respond to a specific lower intensity field by emitting light of a given wavelength.  A subject’s brain could be infused with the nanoparticles, and particles within specific regions of the brain subsequently programmed to respond to stimuli that might be distinguished in terms of their frequency, intensity or time/phase modulation.  All that would then be needed to “control the mind” of the subject would be to subject them to electromagnetic fields with the appropriate characteristics – and this is the important part – without needing a high level of spatial resolution.

In effect, once programmed, a simple wide-field transmitter could be used to send signals to very specific parts of the subject’s brain.  And if the responses weren’t quite what was wanted, there is no reason why the nanoparticles couldn’t be reset, ready for the next round of programming. In other words, you would have the neural equivalent of an old-style computer EPROM (Erasable Programmable Read Only Memory) – an Erasable Programmable Nanoparticle Optogenetic Control device, or EPNOC!

Plausible?

Borderline most likely I suspect.  But not beyond the realms of possibility.

Delivery of spatially dense and highly localized pulses of light is key to optogenetics being used for sophisticated mind control.  If we cannot achieve it, the technique is likely to remain a blunt – albeit still very valuable – instrument.  But if technology platforms such as nanotechnology do begin to converge more fully with optogenetics, we may see some interesting, possibly startling and undoubtedly challenging advances over the coming decades.

Maybe not mind control, but certainly more brain manipulation than has ever before been in our grasp.